Reviews in Endocrine & Metabolic Disorders 2002;3:55±63 # 2002 Kluwer Academic Publishers. Manufactured in The Netherlands. The Ovarian Gonadotropin Receptors in Health and Disease Paul A. Fowler and Ilpo T. Huhtaniemi Department of Obstetrics and Gynaecology, University of Aberdeen, Aberdeen AB25 2ZD, Scotland, UK Key Words. gonadotropin receptors, luteinizing hormone, follicle- stimulatinghormone,hypogonodism,precociouspuberty,infertility Introduction The actions of the two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH), are pivotal for normal ovarian function. In both cases these effects are exerted on their target cells thorough speci®c G-protein associated seven transmembrane domain receptors [1±3]. A third pituitary hormone, prolactin (PRL), can also be considered a gonadotropin in some species, due to its direct gonadal action. However, such effects have not been unequivocally demonstrated in humans. The identi®cation of the genes of gonadotropin receptors (R) has made it possible to explore further details in the physiology of their action as well as to unravel the molecular pathogenesis of speci®c types of gonadal dysfunction, caused either by activating or inactivating mutations of gonadotropin receptors. Phenotypic consequences of the human mutations have been corroborated using genetically modi®ed mouse models, i.e., transgenic mice overexpressing LH or FSH, or knockouts of the FSH and LH ligand and receptor genes. The present review summarizes brie¯y the current concepts about physiological function of ovarian gonadotropin receptors, as well as the currently available information on the human gonadotropin receptor mutations as well as the relevant animal models for diseases affecting the function of gonadotropin receptors. Normal Function of Gonadotropin Receptors Gonadotropin receptor structure and signaling LH (and hCG) and FSH operate through cell-surface G- protein-coupled receptors with seven transmembrane domains, and the cDNAs of their human forms were cloned early in the last decade [4,5]. Both receptors are unique in having a large extracellular domain which is involved in hormone recognition and binding [6,7]. They also have leucine-rich repeat motifs in this domain with divergent sequences which are important for hormone speci®city [8]. The FSHR and LHR genes consist of 10 and 11 exons respectively: the ®rst 9 and 10 exons encoding the extracellular domains while exons 10 (FSHR) and 11 (LHR) encode the transmembrane and intracellular domains [1,2]. Structural studies of the LHR have been hampered by dif®culties in expressing high af®nity receptors, but the recent development of a soluble hCG±LHR complex [9] suggests that a crystalization strategy may be within reach.DetailedunderstandingoftheLHRstructurewould have two bene®ts. First, improved understanding of the receptor structure±function relationships and second, the possibilitythatspeci®cLHagonistsandantagonistscould be developed. These would have tremendous clinical potential. Both LHR and FSHR [10] mRNAs undergo complex alternative splicing, but the functional signi®- cance of these phenomena remains uncertain. The PRLR is a member of the cytokine receptor superfamily, and it exists in at least three differentially spliced rodent forms: long, intermediate and short [11], complicated by the occurrence of multiple mRNA tran- scripts [12]. The PRLR is a transmembrane protein with threestructuralmotifsintheintracellulardomain[13]and functions through dimerization of two receptor molecules binding to different ligand sites on PRL itself [14]. This leads to activation of the tyrosine JAK2 kinase and signal transducers and activators of transcription (STAT) proteins, with the receptor therefore acting via the JAK- STATpathway.MAPkinaseandothersecondmessengers are also involved in PRLR signal transduction [15]. Gonadotropin receptor expression in the ovary Ovarian expression of LHR, FSHR and PRLR is sum- marized in Table 1. The ontogeny of FSHR expression is striking,withnoexpressioninprimordialhumanfollicles, expression in 33% of primary and two-layer follicles and 100% expression in multilaminar follicles [16]. This re¯ectstheexpressionofFSHRingrowingfolliclesrather thaninthepassiveprimordialreserve,especiallysincethe binding activity of FSHR does not change during the menstrual cycle [17]. To date granulosa cells are the only ovarian cell type to express FSHR [18]. Address correspondence to: Ilpo T. Huhtaniemi. 55